Original Research

Association Between Stillbirth and Illicit Drug

Use and Smoking During Pregnancy
Michael W. Varner, MD, Robert M. Silver, MD, Carol J. Rowland Hogue, PhD, Marian Willinger, PhD,
Corette B. Parker, DrPH, Vanessa R. Thorsten, MPH, Robert L. Goldenberg, MD, George R. Saade, MD,
Donald J. Dudley, MD, Donald Coustan, MD, Barbara Stoll, MD, Radek Bukowski, MD,
Matthew A. Koch, MD, PhD, Deborah Conway, MD, Halit Pinar, MD, and Uma M. Reddy, MD, MPH, for the
Eunice Kennedy Shriver National Institute of Child Health and Human Development Stillbirth
Collaborative Research Network*
OBJECTIVE: To compare illicit drug and smoking use in
pregnancies with and without stillbirth.
METHODS: The Stillbirth Collaborative Research Network conducted a casecontrol study from March 2006
to September 2008, covering more than 90% of deliveries
to residents of five a prioridefined geographically diverse
regions. The study attempted to include all stillbirths and
representative liveborn controls. Umbilical cord samples
from cases and controls were collected and frozen for
subsequent batch analysis. Maternal serum was collected
at delivery and batch analyzed for cotinine.
RESULTS: For 663 stillbirth deliveries, 418 (63%) had
cord homogenate and 579 (87%) had maternal cotinine
assays performed. For 1,932 live birth deliveries, 1,050
(54%) had cord homogenate toxicology and 1,545 (80%)
had maternal cotinine assays performed. A positive cord
homogenate test for any illicit drug was associated with
stillbirth (odds ratio [OR] 1.94, 95% confidence interval
From the *For a list of other members of the Stillbirth Collaborative Research
Network, see the Appendix online at http://links.lww.com/AOG/A455.
From the University of Utah School of Medicine, Salt Lake City, Utah; Rollins
School of Public Health, Emory University, and Emory University School of
Medicine, Atlanta, Georgia; the Pregnancy and Perinatology Branch, Eunice
Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; RTI International,
Research Triangle Park, North Carolina; Columbia University, New York,
New York; the University of Texas Medical Branch at Galveston, Galveston,
and the University of Texas Health Science Center at San Antonio, San Antonio,
Texas; and Brown University School of Medicine, Providence, Rhode Island.
Supported by grant funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health:
U10-HD045953 (Brown University, Providence, Rhode Island); U10HD045925 (Emory University, Atlanta, Georgia); U10-HD045952 (University of Texas Medical Branch at Galveston, Galveston, Texas); U10-HDO45955
(University of Texas Health Sciences Center at San Antonio, San Antonio,
Texas); U10-HD045944 (University of Utah Health Sciences Center, Salt Lake
City, Utah); and U01-HD045954 (RTI International, Research Triangle Park,
North Carolina).

VOL. 123, NO. 1, JANUARY 2014

[CI] 1.163.27). The most common individual drug was

cannabis (OR 2.34 95% CI 1.134.81), although the effect
was partially confounded by smoking. Both maternal selfreported smoking history and maternal serum cotinine
levels were associated in a doseresponse relationship
with stillbirth. Positive serum cotinine less than 3 ng/mL
and no reported history of smoking (proxy for passive
smoke exposure) also were associated with stillbirth (OR
2.06, 95% CI 1.243.41).
CONCLUSION: Cannabis use, smoking, illicit drug use,
and apparent exposure to second-hand smoke, separately
or in combination, during pregnancy were associated with
an increased risk of stillbirth. Because cannabis use may be
increasing with increased legalization, the relevance of
these findings may increase as well.
(Obstet Gynecol 2014;123:11325)
DOI: 10.1097/AOG.0000000000000052

LEVEL OF EVIDENCE: II

The authors thank the following members of the Eunice Kennedy Shriver
National Institute of Child Health and Human Development Scientific Advisory
and Safety Monitoring Board for their review of the study protocol, materials, and
progress: Reverend Phillip Cato, PhD; James W. Collins, Jr, MD, MPH; Terry
Dwyer, MD, MPH; William P. Fifer, PhD; John Ilekis, PhD; Marc Incerpi, MD;
George Macones, MD, MSCE; Richard M. Pauli, MD, PhD; Raymond W.
Redline, MD; Elizabeth Thom, PhD (chair) as well as all of the other physicians,
study coordinators, research nurses, and patients who participated in the Stillbirth Collaborative Research Network.
Presented in part at the 2011 Society for Maternal-Fetal Medicine annual meeting, February 1012, 2011, San Francisco, California.
Corresponding author: Michael W. Varner, MD, Department of Obstetrics and
Gynecology, University of Utah Health Sciences Center, 30 North 1900 East, Room
2B200, Salt Lake City, UT 84132; e-mail: Michael.varner@hsc.utah.edu.
Financial Disclosure
The authors did not report any potential conflicts of interest.
2013 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/14

OBSTETRICS & GYNECOLOGY

113

he second half of the 20th century witnessed a substantial decrease in the perinatal mortality rate in
the United States. Although the U.S. stillbirth rate also
gradually decreased during this epoch, from 18 per
1,000 births in 1950 to 6.05 per 1,000 births in 2006,1
this decrease has been substantially less in comparison
to neonatal mortality and the stillbirth rate remains
higher than that of many other developed countries.
In fact, the U.S. stillbirth rate is similar to the neonatal
death rate (6.51/1,000 births) and affects almost
26,000 neonates per year.1
Smoking and drug abuse during pregnancy are
potential modifiable risk factors for stillbirth.212 However, the association between smoking and illicit drugs
and stillbirth is primarily based on studies relying on
self-reporting of smoking and drug abuse. Our objective was to determine the association of smoking and
illicit drug use to stillbirth by measurement of metabolites in maternal serum and umbilical cord homogenate in deliveries complicated by stillbirth compared
with live births.

PATIENTS AND METHODS

The Stillbirth Collaborative Research Network of the
Eunice Kennedy Shriver National Institute of Child Health
and Human Development conducted a populationbased casecontrol study of stillbirth (fetal death
20 weeks of gestation or greater) in five a prioridefined
geographically diverse regions with screening and
enrollment at the time of delivery between March
2006 and September 2008. Details of methods and
study design13 and sample size considerations14 have
been published previously. Attempts were made to
enroll all eligible women whose delivery resulted
in one or more stillborn fetuses and a representative
sample of eligible women whose delivery resulted in
only liveborn neonates supplemented by oversampling of women with live births delivering at less
than 32 weeks of gestation and those of African
descent delivering at 32 weeks of gestation or
greater.13 Approval was obtained from the institutional review board of each clinical site and the data
coordinating center. An advisory board reviewed the
progress and safety of the study. All participants
gave written informed consent.
A stillborn fetus was defined by Apgar scores of
0 at 1 and 5 minutes and no signs of life by direct
observation. Deliveries resulting from the intentional
termination of a live fetus were excluded. Gestational
age was determined by the best clinical estimate using
multiple sources including assisted reproduction (if
applicable), first day of the last menstrual period, and
obstetric ultrasonograms as previously described.15

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Stillbirths and live births were classified as small for

gestational age (SGA) if the birth weight was less than
the tenth percentile for gestational age based on population norms.16
Study components included a comprehensive
standardized fetal postmortem examination and
uniform placental pathology evaluation performed
by a perinatal pathologist.17,18 A standardized maternal interview during the delivery hospitalization and
detailed chart abstraction of prenatal office visits,
antepartum hospitalizations, and the delivery hospitalization were conducted. Biospecimens collected
included maternal blood for serum and DNA, fetal
blood from the umbilical cord (when available), placental tissue, and, in cases, fetal tissue. The consent
process provided participants the option to decline
consent to one or more components of the study: interview, chart abstraction, blood draw, placental examination, autopsy, genetic studies, storage and future use
of biospecimens, and future contact for additional
research. The consent form discussed planned testing
of the afterbirth for legal and illegal drugs, the deidentification of results, and the protections afforded by the
Certificate of Confidentiality that had been obtained
for the study. No special consent was obtained for
cotinine or toxicology testing.
Umbilical cord segments from cases and controls
were collected in sterile containers and frozen at 280C
until assay. Cords were homogenized before batch
enzyme-linked immunosorbent analyses for amphetamine, methamphetamine, cocaine (benzoylecgonine),
pethidine, meperidine, hydrocodone, and tetrahydrocannabinolic acid. All samples were initially tested by
enzyme-linked immunosorbent analysis and presumptive positives were confirmed using appropriate mass
spectrometric assays using established and validated
procedures.19
Maternal blood for serum samples was collected at
delivery and centrifuged for 15 minutes at 1,300 g at
room temperature at all participating clinical sites.
Serum samples were then frozen at 280C until assay.
After completion of the study enrollment, serum aliquots were shipped to the University of Utah Center
for Human Toxicology and batch-analyzed for cotinine
using solid-phase extraction and liquid chromatography.
The personnel performing the assays were blinded to
clinical outcomes.
Medical records from all deliveries with positive cord homogenate narcotic results were reviewed for evidence of prescribed narcotic
administration for any reason before delivery.
Only those with positive cord homogenate testing
and medical records with no evidence of narcotic

OBSTETRICS & GYNECOLOGY

administration before delivery were considered

positive for illicit narcotic use.
Nicotine and cotinine metabolism is accelerated
in pregnancy20 and the maternal serum cotinine per
cigarette ratio is typically less in pregnant compared
with nonpregnant women.21 Thus, the threshold for
defining exposure may be different in pregnant and
nonpregnant women. We addressed this issue by
using quartiles, established in our controls, in addition
to a 3-ng/mL threshold to assess cotinine exposure.22
A positive serum cotinine less than 3 ng/mL in
women who denied smoking was used as a proxy
for passive exposure among nonsmokers.22
The delivery, defined as a case if there were any
stillbirths delivered and as a control if all live births
were delivered, was the unit of analysis. The analyses
were weighted for the oversampling of live births and
other aspects of the study design as well as for
differential consent among the women with stillbirth
and among the women with live birth using SUDAAN
11.0 software.23 The construction of the weights has
been previously described.13 The weighted samples of
live births and stillbirths are intended to approximate random selections of live births and stillbirths
in the catchment areas over the enrollment period.
Crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from univariate and multivariable logistic regression models,
respectively. Predictor variables in the models were
treated as categorical. However, for ordered categories
on smoking history in the trimester, the neonate was
born, and cotinine levels, tests for linear and quadratic
trends in the log odds of stillbirth were also conducted
using orthogonal contrasts. All tests were performed at
a nominal significance level of a50.05. All single
degree-of-freedom tests were two-sided without correction for multiple comparisons.
Adjusted ORs were computed to account for
stillbirth risk factors known at pregnancy confirmation (baseline) using a modification to a risk factor
score for stillbirth that was developed on the logit
scale using the coefficients from a logistic regression
model. Variables contributing to the baseline risk
factor score were those described previously,14 specifically the following maternal characteristics: age,
race or ethnicity, marital status, education, pregnancy
history, body mass index, smoking status, alcohol use,
illicit drug use, hypertension, diabetes, seizure disorder, blood type, Rh factor, and multiple gestation in
current pregnancy as well as paternal age, family
income, insurance or method of payment, and clinical
site. All variables included in the score were categorical and an average of the regression coefficients

VOL. 123, NO. 1, JANUARY 2014

associated with the categories was used when a variable was missing for an observation. The average was
based on the sample-weighted proportion of live
births by category. The modification to the risk factor
score for this analysis was to exclude coefficients associated with smoking status and illicit drug use.
The relationships among cotinine levels (negative, 50th percentile or less, greater than 50th percentile), tetrahydrocannabinolic acid, and SGA fetus on
pregnancy outcome were studied by comparing the
stillbirth ORs for one of the factors with and without
accounting for another in logistic regression models.
A commonly used threshold of 10% reduction (or
increase) in the OR was taken as a measure of confounding. In addition, the interactions of high levels of
cotinine (greater than 50th percentile) with an SGA
fetus and with preeclampsia were studied using logistic regression models with an interaction term and
computing stillbirth ORs for high cotinine levels stratified by whether the fetus was SGA and by whether
preeclampsia was a condition noted in the chart at
delivery.

RESULTS
Enrollment to the Stillbirth Collaborative Research
Network study and inclusion in the serum cotinine
and toxicology analyses are shown in Figure 1. For
663 stillbirth deliveries (cases), 418 (63%) had a cord
segment collected for subsequent toxicology studies
and 579 (87%) had maternal serum analyzed for cotinine. More than half (380 [57%]) had both maternal
serum and cord segments for analysis. For 1,932 live
birth deliveries (controls), 1,050 (54%) had cord segments collected for subsequent toxicology studies and
1,545 (80%) had maternal serum analyzed for cotinine. Approximately half (891 [46%]) had both maternal serum and cord segments for analysis. Cotinine
and toxicology testing was done on virtually all
women with adequate blood or cord collected.
Absence or insufficient sample was the result of the
participant declining sample collection, inconvenient
timing, administrative error, and in the vast majority
of cases for umbilical cord, discarding of the placenta
before it could be retrieved for examination.
Table 1 shows characteristics of cases and controls
that did, and did not, undergo cotinine testing and
toxicology screening. For both groups, those with cotinine testing, toxicology screening, or both were more
likely to be non-Hispanic white and less likely to be
non-Hispanic black than those without testing. Participants in the case group and those in the control group
with both cotinine testing and toxicology screening
were more likely to have commercial insurance and

Varner et al

Smoking, Illicit Drugs, and Stillbirth

115

Not approached
n=126

Eligible stillbirth
pregnancies
N=953

Refused
n=164
Enrolled
n=663; 70%

Cotinine testing
n=579; 87%

No cotinine testing
n=84; 13%

Toxicology screening
n=418; 63%

No toxicology
screening
n=245; 37%

A
Requires maternal serum

Requires umbilical cord

Not approached
n=394

Cotinine testing
and toxicology
screening
n=380; 57%

No cotinine testing
or toxicology
screening
n=283; 43%

Requires maternal serum

and umbilical cord

Eligible live birth

pregnancies
N=3,088

Refused
n=762
Enrolled
n=1,932; 63%

Cotinine testing
n=1,545; 80%

No cotinine testing
n=387; 20%

Requires maternal serum

Toxicology screening
n=1,050; 54%

No toxicology
screening
n=882; 46%

Requires umbilical cord

Cotinine testing
and toxicology
screening
n=891; 46%

No cotinine testing
or toxicology
screening
n=1,041; 54%

Requires maternal serum

and umbilical cord

Fig. 1. Cotinine and toxicology analyses comparing results from stillbirth and live birth pregnancies. The Stillbirth Collaborative Research Network stillbirth case status is defined as follows. A pregnancy is categorized as a stillbirth pregnancy if
there are any stillbirths delivered and as a live birth pregnancy if all live births are delivered. A fetal death is defined by
Apgar scores of 0 at 15 minutes and no signs of life by direct observation. Fetal deaths are classified as stillbirths if the best
clinical estimate of gestational age at death is 20 or more weeks. Fetal deaths at 1819 weeks of gestation without good
dating are also included as stillbirths.
Varner. Smoking, Illicit Drugs, and Stillbirth. Obstet Gynecol 2014.

deliver at later gestational ages. Also, a disproportionate

number of participants in the control group with testing
were between 20 and 39 years of age compared with
those without testing.
Women who self-reported smoking were more
likely than those who did not to be non-Hispanic
white, 2034 years of age, of low education, unmarried, and low income. Those who self-reported drug
use were more likely than women who did not to be
non-Hispanic white and unmarried (data not shown).
Self-reported smoking and drug use, cotinine
levels, and cord homogenate findings in all stillbirth
and live birth deliveries are depicted in Table 2.
There was an increase in the stillbirth OR with

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increasing amounts of self-reported smoking in the

trimester the neonate was born (linear trend P,.004).
Compared with women who never smoked, women
who reported smoking one to nine cigarettes per day
had a 1.77 OR for stillbirth (95% CI 1.132.80); and
those smoking 10 or more cigarettes per day had an
OR for stillbirth of 2.17 (95% CI 1.253.78). Similar
results were noted with serum cotinine levels. Compared with women testing negative, those with positive cotinine concentrations 50th percentile or less
had an OR of 2.04 (95% CI 1.393.01); and those
with cotinine levels greater than 50th percentile had
an OR of 2.39 (95% CI 1.623.52) (linear trend
P,.001). Similar results were noted if cotinine

OBSTETRICS & GYNECOLOGY

Table 1. Sociodemographic and Pregnancy Characteristics by Cotinine Testing and Toxicology Screening
Status

CharacteristicWeighted
Percentage*

Cotinine Testing
No

Yes

Toxicology Screening
No

Yes

Stillbirth pregnancies
Unweighted sample size (n)
84
579
245
418
87
576
258
405
Weighted sample size (nw)
Maternal age at delivery (y)
Younger than 20
13.9
13.1
.666 15.3
11.8
.357
2034
67.1
70.1
70.3
69.3
3539
15.9
11.9
10.0
13.9
40 or older
3.1
5.0
4.4
4.9
Maternal race or ethnicity
White, non-Hispanic
18.4
35.7 ,.001 19.3
42.5 ,.001
Black, non-Hispanic
41.5
20.6
31.8
17.9
Hispanic
31.3
37.1
40.9
33.3
Other
8.8
6.7
8.0
6.3
Insurance or method of payment
No insurance
9.7
5.4
.290
6.9
5.3
.020
Any public or private assistance
50.8
54.0
59.5
49.8
Veterans Affairs, commercial health 39.6
40.7
33.6
44.9
insurance, or HMO
Gestational age (wk)
1819
3.6
2.3
.123
4.7
1.1
.028
2023
46.3
32.0
38.2
31.1
2427
16.5
15.7
15.8
15.9
2831
10.9
13.0
9.7
14.6
3236
11.2
19.9
17.2
19.8
37 or more
11.4
17.0
14.4
17.5
Live-birth pregnancies
Unweighted sample size (n)
387
1,545
882
1,050
256
1,183
565
874
Weighted sample size (nw)
Maternal age at delivery (y)
Younger than 20
13.9
9.5
.029 11.7
9.4
.465
2034
71.4
76.6
75.0
76.1
3539
10.6
12.2
11.1
12.5
40 or more
4.1
1.7
2.2
2.0
Maternal race or ethnicity
White, non-Hispanic
38.9
47.3 ,.001 36.1
52.1 ,.001
Black, non-Hispanic
22.5
9.4
18.8
7.2
Hispanic
29.2
36.1
37.8
32.9
Other
9.4
7.2
7.4
7.8
Insurance or method of payment
No insurance
3.1
3.6
.476
3.9
3.4
.022
Any public or private assistance
52.1
47.9
53.2
45.7
Veterans Affairs, commercial health 44.8
48.5
43.0
50.9
insurance, or HMO
Gestational age (wk)
2023
0.3
0.4
.291
0.5
0.3 ,.001
2427
1.0
0.7
1.4
0.3
2831
1.2
1.0
2.0
0.4
3236
10.6
8.2
13.0
5.8
37 or more
86.9
89.8
83.1
93.2

Cotinine Testing Toxicology

Screening
No
283
296

Yes

380
367

15.9
69.2
10.8
4.1

11.0
70.1
13.7
5.2

.256

20.2
32.8
39.5
7.5

44.1
15.7
33.7
6.5

,.001

8.0
57.9
34.1

4.3
50.1
45.7

.005

4.1
39.1
15.8
9.7
16.7
14.6

1.2
29.6
15.9
15.2
20.5
17.6

.014

1,041
697

891
742

12.4
73.9
10.9
2.8

8.4
77.3
12.9
1.5

.019

37.9
17.4
36.7
8.0

53.2
6.4
33.1
7.2

,.001

3.5
44.5
52.0

.007

0.3
0.3
0.4
5.8
93.2

,.001

3.6
53.1
43.4

0.4
1.2
1.7
11.6
85.1

HMO, health maintenance organization.

* Weighted percentages and P values are shown by analysis inclusion status, ie, whether specific testing (cotinine, toxicology, cotinine, and
toxicology) was done. The weights take into account the study design and differential consent based on characteristics recorded on all
eligible pregnancies that were screened for the study. Unweighted and weighted samples sizes are also provided. The weighted sample
sizes are not integers but are shown rounded to the nearest integer. Sample sizes vary slightly by characteristic included in the table. Nw
is a count of the observations according to their relative weight in the analysis.

VOL. 123, NO. 1, JANUARY 2014

Varner et al

Smoking, Illicit Drugs, and Stillbirth

117

Table 2. Maternal Report and Testing Results for Smoking and Drug Use by Stillbirth Collaborative
Research Network Case Status
CharacteristicWeighted Percentage*
Maternal report of smoking
Unweighted sample size (n)
Weighted sample size (nw)
Smoked trimester the neonate was born (%)
No, never smoked
No, smoked previously
Yes, 19 cigarettes/d on average
Yes, 10 or more cigarettes/d on average
Test: linear trend
Cotinine testing
Unweighted sample size (n)
Weighted sample size (nw)
Positive for cotinine (%)
Cotinine concentration (ng/mL) (%)
Negative (less than 0.25)
Positive, less than 3
Positive, 3 or higher
Test: linear trend
Cotinine concentration (ng/mL) by quartile for positives (%)
Negative (less than 0.25)
Positive, 1.49 or less
Positive, 1.499.68
Positive, 9.6823.62
Positive, greater than 23.62
Test: linear trend
Cotinine concentration (ng/mL) by median for positives (%)
Negative (less than 0.25)
Positive, 50th percentile or less (9.68 or less)
Positive, greater than 50th percentile (greater than 9.68)
Test: linear trend
Maternal report of smoking and cotinine testing
Unweighted sample size (n)
Weighted sample size (nw)
Cotinine and smoking during the trimester the neonate was born (%)
Negative cotinine (less than 0.25) and never smoked
Negative cotinine (less than 0.25) and smoked previously
Negative cotinine (less than 0.25) and smoked
Positive cotinine, less than 3 ng/mL, and did not smoke
Positive cotinine, 3 or more ng/mL, and did not smoke
Positive cotinine, any concentration, and smoked
Cotinine and smoking during the trimester the neonate was born (%)
Negative cotinine (less than 0.25) and never smoked
Negative cotinine (less than 0.25) and smoked previously
Negative cotinine (less than 0.25) and smoked
Positive cotinine, 50th percentile or less (9.68 ng/mL or less), and
did not smoke
Positive cotinine, greater than 50th percentile (greater than
9.68 ng/mL), and did not smoke
Maternal report of lifetime drug use
Unweighted sample size (n)
Weighted sample size (nw)
Lifetime drug use (%)
Reported never used drugs
Reported drug use
Without addiction
With addiction

Stillbirth

Live Birth

613
614

1,832
1,366

81.1
8.8
5.9
4.2

87.1
7.2
3.6
2.1

Odds Ratio (95% CI)

Reference
1.31 (0.921.86)
1.77 (1.132.80)
2.17 (1.253.78)

.002

.003
579
576
18.5

1,545
1,183
9.3

2.22 (1.672.95)

,.001

81.5
6.4
12.1

90.7
3.3
6.0

Reference
2.16 (1.393.37)
2.25 (1.593.19)

,.001

81.5
4.8
3.5
4.1
6.0

90.7
2.3
2.3
2.4
2.4

Reference
(1.403.97)
(0.993.03)
(1.103.47)
(1.694.67)

,.001

2.36
1.73
1.96
2.81

,.001

.004
Reference
2.04 (1.393.01)
2.39 (1.623.52)

,.001

Reference
(0.661.65)
(0.202.72)
(1.243.41)
(1.394.88)
(1.543.43)

,.001

84.5
5.6
0.8
3.5

Reference
1.04 (0.661.65)
0.73 (0.202.72)
1.89 (1.193.00)

,.001

2.7

0.8

3.84 (1.748.46)

611
610

1,823
1,349

67.2

69.3

28.1
4.7

28.6
2.1

81.5
8.4
10.1

90.7
4.5
4.7

548
546

1,489
1,144

75.8
5.3
0.5
5.0
3.6
9.8

84.5
5.6
0.8
2.7
1.5
4.8

1.04
0.73
2.06
2.61
2.30

75.8
5.3
0.5
5.9

Reference

,.001

.007

1.01 (0.811.26)
2.30 (1.373.86)
(continued )

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OBSTETRICS & GYNECOLOGY

Table 2. Maternal Report and Testing Results for Smoking and Drug Use by Stillbirth Collaborative
Research Network Case Status (continued )
CharacteristicWeighted Percentage*

Stillbirth

Live Birth

418
405
7.0

1,050
874
3.7

1.3
0.0
0.6
0.4
0.0
3.9
0.9
0.7

0.4
0.0
0.2
0.0
1.0
1.7
0.6
0.1

93.0
6.2
0.8

96.3
3.5
0.2

384
373

980
813

64.8
28.3
2.1
4.8

68.4
28.2
1.9
1.5

380
367

891
742

80.6
12.4
3.3
3.8

88.6
8.0
2.4
1.1

Odds Ratio (95% CI)

Toxicology screening
Unweighted sample size (n)
Weighted sample size (nw)
Positive for any drug (%)
Positive for specific drugs (%)
Morphine
Hydromorphone
Codeine
Hydrocodone
Pethidine or meperidine
Tetrahydrocannabinolic acid
Cocaine (benzoylecgonine)
Amphetamine or methamphetamine
None, single or multiple drugs detected (%)
Negative for all drugs
Positive for 1 drug
Positive for 2 drugs
Maternal report of lifetime drug use and toxicology screening
Unweighted sample size (n)
Weighted sample size (nw)
Umbilical cord toxicology and lifetime drug use (%)
Negative for all drugs and reported never used drugs
Negative for all drugs and reported drug use
Positive for any drug and reported never used drugs
Positive for any drug and reported drug use
Cotinine testing and toxicology screening
Unweighted sample size (n)
Weighted sample size (nw)
Cotinine and drug use (%)
Negative cotinine (less than 0.25) and negative for all drugs
Positive cotinine and negative for all drugs
Negative cotinine (less than 0.25) and positive for any drug
Positive cotinine and positive for any drug

1.94 (1.163.27)

.012

3.46 (0.8613.90)
.080

2.80 (0.3920.27)
.307
152.57 (13.731,695.65) ,.001

2.34 (1.134.81)
.021
1.59 (0.416.14)
.501
8.17 (0.8479.68)
.071
Reference
1.83 (1.063.15)
3.69 (0.6421.31)

.033

Reference
1.06 (0.801.41)
1.19 (0.502.84)
3.30 (1.547.03)

.023

Reference
1.70 (1.132.56)
1.53 (0.713.27)
3.86 (1.619.24)

.001

CI, confidence interval.

* Weighted percentages, odds ratios, and P values are shown. The weights take into account the study design and differential consent based
on characteristics recorded on all eligible pregnancies that were screened for the study. Unweighted and weighted samples sizes are also
provided. The weighted sample sizes are not integers but are shown rounded to the nearest integer. For ordered categories on smoking
history in the trimester, the neonate was born, and cotinine levels, tests for linear and quadratic trends in the log odds of stillbirth were
conducted using orthogonal contrasts. None of the quadratic trends was significant and their P values are not reported. Nw is a count of
the observations according to their relative weight in the analysis.

Previously indicates that the mother reported smoking 3 months before pregnancy or during pregnancy, but not during the trimester the
neonate was born.

Lower limit of detectability for the cotinine assay.

The toxicology screening panel can detect amphetamines (amphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxy-Nethylamphetamine, N,N-dimethyldopamine, and methamphetamine), cannabinoids, cocaine (benzoylecgonine), opiates (codeine,
hydrocodone, hydromorphine, morphine, 6-monoacetylmorphine, and meconin), phencyclidine (phencyclidine), 2-ethylidene1,5-dimethyl-3,3-diphenylpyrrolidine, methadone, and barbiturates (amobarbital, butalbital, pentobarbital, phenobarbital, and
secobarbital).

concentrations between 0.25 and 2.99 and 3.00+

were used (linear trend P,.001). Women who
denied smoking but had elevated cotinine levels
had increased odds for stillbirth using either the 3ng/mL cut point or percentiles (eg, positive cotinine
less than 3 ng/mL OR 2.06, 95% CI 1.243.41; positive cotinine greater than 3 ng/mL OR 2.61, 95% CI
1.394.88).

VOL. 123, NO. 1, JANUARY 2014

Women with stillbirth were twice as likely as

those with a live birth to report having been addicted
to an illicit drug (OR 2.30, 95% CI 1.373.86). A
positive test for any drug in the cord homogenate
was associated with an OR for stillbirth of 1.94 (95%
CI 1.163.27). The OR was higher in women having
a positive toxicology screen who also reported ever
using illicit drugs (OR 3.30, 95% CI 1.547.03). The

Varner et al

Smoking, Illicit Drugs, and Stillbirth

119

most common individual drug, tetrahydrocannabinolic acid, was positive in 3.9% of participants in the
case group and 1.7% of participants in the control
group (OR for stillbirth 2.34, 95% CI 1.134.81).
Among women with testing for cotinine and illicit
drugs, women who were positive for cotinine and
not illicit drugs had an OR of 1.70 (95% CI 1.13
2.56) compared with those who were negative for
both; and women who were positive for both had
an OR of 3.86 (95% CI 1.619.24). However, the
ORs for positive for both compared with positive
for cotinine only were not significantly different and
there was evidence of confounding of the relationship
between illicit drugs and stillbirth by cotinine.
Because they were already at higher risk for
complications, we anticipated that smoking and illicit
drugs would have less influence on pregnancies
complicated by multiple gestation, obstetric complications, or fetal aneuploidy. We therefore repeated
these analyses in nonanomalous, singleton pregnancies excluding intrapartum stillbirths, as shown in
Table 3. The OR for stillbirth in women with positive
cotinine levels 50th percentile or less was 1.88 (95% CI
1.192.97) and for those with levels greater than the
50th percentile was 2.67 (95% CI 1.754.07). Women
with any positive toxicology screen had an increased
odds of stillbirth of 2.23 (95% CI 1.293.88). Positive
cord homogenate tetrahydrocannabinolic acid was
associated with an increased odds of stillbirth of 2.83
(95% CI 1.345.99).
Selected ORs adjusted for prepregnancy risk
factors for stillbirth are shown in Table 4. Self-reported smoking and elevated levels of cotinine were
associated with stillbirth even after adjustment for
other known risk factors. The adjusted OR for stillbirth with positive cotinine levels 50th percentile or
less was 2.05 (95% CI 1.333.17) and for cotinine
levels greater than 50th percentile was 2.56 (95% CI
1.663.93). A positive test for drug use also was associated with stillbirth after adjustment. The adjusted
results were also significant in the subgroup of nonanomalous, singleton pregnancies excluding intrapartum stillbirths. There were too few cases of positive
results to assess adjusted ORs for each individual illicit
drug.
Adjusting for whether the fetus was SGA reduced
the stillbirth OR for cotinine (50th percentile or less
compared with negative and greater than the 50th percentile compared with negative) by greater than 10%.
Thus, at least part of the association between smoking
and stillbirth is mediated through fetal growth restriction. Furthermore, the interaction between high cotinine levels and fetal SGA was significant (P,.02) and

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Smoking, Illicit Drugs, and Stillbirth

the stillbirth ORs for high cotinine levels among SGA

and non-SGA fetuses were 2.43 (95% CI 1.533.86)
and 0.81 (95% CI 0.361.82), respectively. In contrast,
there was no significant interaction between high cotinine levels and preeclampsia in association with
a stillbirth outcome of pregnancy.
Adjusting for cotinine level reduced the stillbirth
OR for tetrahydrocannabinolic acid by greater than
10%, but adjusting for tetrahydrocannabinolic acid
did not reduce the stillbirth ORs for cotinine level.
Thus, we cannot exclude the possibility that the
association between cannabis and stillbirth is partially
the result of confounding by tobacco smoke. There
was no evidence of confounding of the relationship
between tetrahydrocannabinolic acid and stillbirth by
SGA fetus.
Among the 1,271 deliveries with both serum
cotinine and drug testing, one woman was human
immunocompromised virus-positive, seven were positive for hepatitis B, and four were positive for
hepatitis C. Only two of these women (both positive
for hepatitis C) had either a positive cotinine or drug
test. These small numbers preclude further analyses of
the relationship between substance abuse and viral
infection.

DISCUSSION
In this population-based study of stillbirth, we noted
a twofold increase in stillbirth in women with positive
umbilical cord homogenate screening. The most
common drug detected was tetrahydrocannabinolic
acid, which was significantly associated with stillbirth
(OR 2.34, 95% CI 1.134.81). The effect was at least
partially confounded with the effects of cotinine. Cannabis remains the most commonly used illicit drug in
the United States. In 2009, 16.7 million persons reported using marijuana within the previous 30 days,
a 2.3 million per month increase from 2007.24 Previous studies of cannabis use in pregnancy have been
based on self-report and either showed no association
with adverse pregnancy outcomes or were associated
with decreased fetal growth.2528
Although numbers were small, hydrocodone and
morphine trended toward an association with an
increased odds of stillbirth, which is important given
the epidemic of prescription opioid drug abuse.29
Approximately 1 in 20 of the U.S. population aged
12 years or older has used opioid pain relievers nonmedically24 and the potential exists that this could
involve substantial numbers of pregnant women.
We also demonstrated a strong association
between maternal smoking and stillbirth. Both selfreported smoking and maternal serum cotinine levels

OBSTETRICS & GYNECOLOGY

Table 3. Maternal Report and Testing Results for Smoking and Drug Use by Stillbirth Collaborative
Research Network Case Status for Nonanomalous, Singleton Pregnancies Excluding Intrapartum
Stillbirths
Characteristic, Weighted Percentage*
Maternal report of smoking
Unweighted sample size (n)
Weighted sample size (nw)
Smoked trimester the neonate was born
No, never smoked
No, smoked previously
Yes, 19 cigarettes/d on average
Yes, 10 or more cigarettes/d on average
Test: linear trend
Cotinine testing
Unweighted sample size (n)
Weighted sample size (nw)
Positive for cotinine
Cotinine concentration (ng/mL)
Negative (less than 0.25)
Positive, less than 3
Positive, 3 or more
Test: linear trend
Cotinine concentration (ng/mL) by quartile for positives
Negative (less than 0.25)
Positive, 1.49 or less
Positive, 1.499.68
Positive, 9.6823.62
Positive, greater than 23.62
Test: linear trend
Cotinine concentration (ng/mL) by median for positives
Negative (less than 0.25)
Positive, 50th percentile or less (9.68 or less)
Positive, greater than 50th percentile (greater than 9.68)
Test: linear trend
Maternal report of smoking and cotinine testing
Unweighted sample size (n)
Weighted sample size (nw)
Cotinine and smoking during the trimester the neonate was born
Negative cotinine (less than 0.25) and never smoked
Negative cotinine (less than 0.25) and smoked previously
Negative cotinine (less than 0.25) and smoked
Positive cotinine, less than 3 ng/mL, and did not smoke
Positive cotinine, 3 or more ng/mL, and did not smoke
Positive cotinine, any concentration, and smoked
Cotinine and smoking during the trimester the neonate was born
Negative cotinine (less than 0.25) and never smoked
Negative cotinine (less than 0.25) and smoked previously
Negative cotinine (less than 0.25) and smoked
Positive cotinine, 50th percentile or less (9.68 ng/mL or less), and did not
smoke
Positive cotinine, greater than 50th percentile (greater than 9.68 ng/mL),
and did not smoke
Maternal report of lifetime drug use
Unweighted sample size (n)
Weighted sample size (nw)
Lifetime drug use
Reported never used drugs
Reported drug use

Stillbirth

Live
Birth

412
405

1,723
1,304

80.4
9.5
6.0
4.1

86.9
7.4
3.7
2.1

Odds Ratio (95% CI)

Reference
1.40 (0.942.07)
1.78 (1.072.97)
2.09 (1.103.94)

.001

.017
396
387
18.9

1,455
1,131
9.2

2.29 (1.663.16)

,.001

81.1
6.0
12.9

90.8
3.2
6.0

Reference
2.12 (1.273.53)
2.39 (1.623.52)

,.001

81.1
4.0
3.4
4.8
6.7

90.8
2.1
2.3
2.5
2.4

Reference
(1.143.94)
(0.873.17)
(1.184.04)
(1.835.53)

,.001

2.12
1.66
2.18
3.18

,.001

.001
Reference
1.88 (1.192.97)
2.67 (1.754.07)

,.001

Reference
(0.721.98)
(0.153.29)
(1.183.73)
(1.526.06)
(1.423.52)

.001

84.6
5.6
0.8
3.3

Reference
1.20 (0.721.98)
0.71 (0.153.29)
1.88 (1.113.19)

,.001

3.3

0.8

4.95 (2.1011.65)

410
402

1,714
1,288

66.6

69.7

81.1
7.4
11.5

90.8
4.4
4.8

371
363

1,404
1,095

75.0
6.0
0.5
4.8
4.1
9.6

84.6
5.6
0.8
2.6
1.5
4.8

1.20
0.71
2.10
3.03
2.24

75.0
6.0
0.5
5.6

,.001

Reference

.017
(continued )

VOL. 123, NO. 1, JANUARY 2014

Varner et al

Smoking, Illicit Drugs, and Stillbirth

121

Table 3. Maternal Report and Testing Results for Smoking and Drug Use by Stillbirth Collaborative
Research Network Case Status for Nonanomalous, Singleton Pregnancies Excluding Intrapartum
Stillbirths (continued )
Characteristic, Weighted Percentage*
Without addiction
With addiction
Toxicology screening
Unweighted sample size (n)
Weighted sample size (nw)
Positive for any drug
Positive for specific drugs
Morphine
Hydromorphone
Codeine
Hydrocodone
Pethidine or meperidine
Tetrahydrocannabinolic acid
Cocaine (benzoylecgonine)
Amphetamine or methamphetamine
None, single, or multiple drugs detected
Negative for all drugs
Positive for 1 drug
Positive for 2 drugs
Maternal report of lifetime drug use and toxicology screening
Unweighted sample size (n)
Weighted sample size (nw)
Umbilical cord toxicology and lifetime drug use
Negative for all drugs and reported never used drugs
Negative for all drugs and reported drug use
Positive for any drug and reported never used drugs
Positive for any drug and reported drug use
Cotinine testing and toxicology screening
Unweighted sample size (n)
Weighted sample size (nw)
Cotinine and drug use
Negative cotinine (less than 0.25) and negative for all drugs
Positive cotinine and negative for all drugs
Negative cotinine (less than 0.25) and positive for any drug
Positive cotinine and positive for any drug

Stillbirth

Live
Birth

28.5
4.9

28.1
2.2

1.06 (0.821.37)
2.33 (1.314.17)

297
284
8.2

993
842
3.8

2.23 (1.293.88)

1.5
0.0
0.4
0.3
0.0
4.9
1.3
0.7

0.4
0.0
0.2
0.0
1.0
1.8
0.6
0.1

91.8
7.3
0.8

96.2
3.6
0.2

270
259

928
784

61.4
30.6
2.7
5.3

68.7
27.7
2.0
1.6

274
262

845
715

78.1
13.5
4.1
4.3

88.8
7.6
2.4
1.1

Odds Ratio (95% CI)

4.19 (0.9318.98)

1.81 (0.1620.31)
95.29 (5.931,531.34)

2.83 (1.345.99)
2.19 (0.578.48)
7.61 (0.6785.98)

.004
.063

.629
.001

.007
.256
.101

Reference
2.14 (1.203.79)
3.71 (0.5425.42)

.015

Reference
1.24 (0.901.70)
1.56 (0.623.87)
3.79 (1.698.53)

.008

Reference
2.02 (1.293.16)
1.94 (0.884.26)
4.35 (1.7410.84)

,.001

CI, confidence interval.

* Weighted percentages, odds ratios, and P values are shown. The weights take into account the study design and differential consent based
on characteristics recorded on all eligible pregnancies that were screened for the study. Unweighted and weighted samples sizes are also
provided. The weighted sample sizes are not integers but are shown rounded to the nearest integer. For ordered categories on smoking
history in the trimester the neonate was born and cotinine levels, tests for linear and quadratic trends in the log odds of stillbirth were
conducted using orthogonal contrasts. None of the quadratic trends was significant and their P values are not reported. Nw is a count of
the observations according to their relative weight in the analysis.

Previously indicates that the mother reported smoking 3 mo before pregnancy or during pregnancy, but not during the trimester the
neonate was born.

Lower limit of detectability for the cotinine assay.

The toxicology screening panel can detect amphetamines (amphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxy-Nethylamphetamine, N,N-dimethyldopamine, and methamphetamine), cannabinoids, cocaine (benzoylecgonine), opiates (codeine, hydrocodone,
hydromorphine, morphine, 6-monoacetylmorphine, and meconin), phencyclidine (phencyclidine), 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, methadone, and barbiturates (amobarbital, butalbital, pentobarbital, phenobarbital, and secobarbital).

were associated with an increased stillbirth risk. Moreover, there was a general doseresponse effect,
strengthening the biological plausibility of the association. These data are similar to other reports associating
self-reported maternal smoking with stillbirth.911 Prior

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Smoking, Illicit Drugs, and Stillbirth

studies also have noted a dose-dependent relationship

between smoking and stillbirth and have demonstrated
ORs in the range of 2.0.10,11,30 In this study, we used
cotinine levels to objectively verify and quantitate
smoking.

OBSTETRICS & GYNECOLOGY

Table 4. Selected Adjusted Stillbirth Odds Ratios for Smoking and Drug Use
Nonanomalous, Singleton
Pregnancies, Excluding
Intrapartum Stillbirths

All Pregnancies
Characteristic*
Cotinine concentration (ng/mL) by median for positives
Negative (less than 0.25)
Positive, 50th percentile or less (9.68 or less)
Positive, greater than 50th percentile (greater than 9.68)
Test: linear trend
Cotinine and drug use
Negative cotinine (less than 0.25) and negative for all drugs
Positive cotinine and negative for all drugs
Negative cotinine (less than 0.25) and positive for any drug
Positive cotinine and positive for any drug

Adjusted OR (95% CI)

Adjusted OR (95% CI)

Reference
2.05 (1.333.17)
2.56 (1.663.93)

,.001

Reference
1.84 (1.113.05)
2.70 (1.724.25)

,.001

Reference
2.08 (1.313.30)
1.39 (0.593.28)
4.53 (1.7112.05)

,.001

Reference
2.46 (1.494.04)
1.89 (0.824.40)
4.00 (1.4510.97)

,.001

,.001

,.001

OR, odds ratio; CI, confidence interval.

* Weighted stillbirth odds ratios and P values are shown for smoking and drug use characteristics after adjustment for stillbirth risk factors
known at pregnancy confirmation. The weights take into account the study design and differential consent based on characteristics
recorded on all eligible pregnancies that were screened for the study. The adjustment for stillbirth risk factors is through a modified risk
factor score for stillbirth developed on the logit scale using coefficients from a logistic regression model. The modification was to
exclude coefficients associated with smoking status and illicit drug use. Weighted (unweighted) samples sizes for observations included
in these adjusted analyses for cotinine are 548 (551) stillbirths and 1,143 (1,497) live births for all pregnancies and 367 (375) and 1,094
(1,410), respectively, for nonanomalous, singleton pregnancies, excluding intrapartum stillbirths. For cotinine and drug use, the sample
sizes are 348 (359) and 708 (855), respectively, for all pregnancies and 246 (257) and 684 (811), respectively, for the subgroup. For
ordered categories on cotinine levels, tests for linear and quadratic trends in the log odds of stillbirth were conducted using orthogonal
contrasts. Neither of the quadratic trends was significant and their P values are not reported.

Lower limit of detectability for the cotinine assay.

The toxicology screening panel can detect amphetamines (amphetamine, e,4-methylenedioxyamphetamine, 3,4-methylenedioxy-Nethylamphetamine, N,N-dimethyldopamine and methamphetamine), cannabinoids, cocaine (benzoylecgonine), opiates
(codeine, hydrocodone, hydromorphine, morphine, 6-monoacetylmorphine, and meconin), phencyclidine (phencyclidine,
2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, methadone), and barbiturates (amobarbital, butalbital, pentobarbital,
phenobarbital, and secobarbital).

We also identified an increased risk of stillbirth

among women exposed to second-hand smoke. We
acknowledge that some of these women may have
actually smoked but that number is likely small.3133
Although recent studies have reported a relationship
between second-hand smoke and stillbirth,3436 none
used cotinine levels to verify and quantify the degree
of exposure.
Our study had several limitations. First, participants who did not have cotinine and toxicology
testing differed in race or ethnicity and gestational
age from those whom samples were available for
testing, which may bias our findings. Second, drug
use during pregnancy declines at term, which may
have been another source of bias. Third, it is unclear
whether exposure occurred before or after the
stillbirth. Finally, despite the large number of women
with stillbirth, we had a relatively small number of
women testing positive for individual drugs. Thus,
we lacked a sample size to make definitive conclusions regarding the relationship between some individual drugs and stillbirth and among cannabis use,
smoking, and stillbirth.

VOL. 123, NO. 1, JANUARY 2014

There were also several strengths of our study.

The study was population-based and racially and
ethnically diverse. In addition, all participants were
evaluated with a thorough standardized protocol
that minimized variability in data and sample collection. Our study also included a maternal interview
and medical record abstraction to allow for in-depth
questions about smoking and drug use. Finally, in
addition to self-reported substance abuse, exposure to
tobacco and illicit drugs was confirmed by analyses
that were blinded to the clinical outcome.
In summary, positive toxicology screen for illicit
drugs was associated with a two- to threefold increase
in stillbirth risk. Documentation of tetrahydrocannabinolic acid indicating cannabis use increased the
odds of stillbirth twofold. Cannabis users often smoke
as well, and more research is needed to investigate the
interaction of tetrahydrocannabinolic acid and cigarette smoking. In addition, positive cotinine levels and
smoking were associated with a twofold to two- to
2.5-fold increase in the risk of stillbirth. Furthermore,
even apparent passive smoking exposure was associated with stillbirth. Between 10% and 30% of

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123

pregnant women in developed countries continue to

smoke during pregnancy.11 Women who quit smoking from their first to second pregnancy have been
shown to reduce their risk of stillbirth to the same
level as nonsmokers in the second pregnancy.37 In
addition, cannabis use remains common during pregnancy with 2% of the women in this study with a positive cord homogenate (among live birth control
participants). Smoking and illicit drugs continue to
be common and important modifiable risk factors for
stillbirth. Because cannabis use may be increasing
with increased legalization, the relevance of our
studys findings may increase as well. Clinicians
should be alert to these risks and should educate
women regarding dangers associated with marijuana
use and active and passive smoke exposure during
pregnancy.
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